Division of Molecular Signaling, Department of the Advanced Biomedical Research, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan. Electronic address: [Email]
Hydrogen sulfide (H2S) is a gaseous mediator with multifaceted biological activities. It has anti-inflammatory and anti-oxidative effects. Currently, the mechanisms are not fully understood. Given that Trx/ASK1/P38 signaling pathway mediates many oxidative cell responses, we tested whether and how H2S affected this pathway. Exposure of podocytes to Adriamycin (ADR), an antitumor drug, led to a P38-mediated oxidative cell injury, as evidenced by the increased protein carbonylation, oxidative activation of P38, and prevention of the cell death by antioxidants, NADPH oxidase inhibitor and P38 inhibitor. In the presence of H2S donor NaHS, however, the podocyte injury was largely prevented. NaHS also significantly prevented cell death elicited by H2O2, menadione, and thioredoxin (Trx) inhibitors. These effects of H2S were also associated with a potent inhibition of P38. Further analysis revealed that H2S did not affect the protein level of TXNIP and Trx, two pivotal regulators of ASK1/P38 activation, but it promoted the dissociation of Trx from TXNIP. Moreover, it disrupted the H2O2-initiated polymerization of Trx and converted Trx from the oxidized to the reduced form. In HepG2 cells, inhibition of H2S-producing enzyme cystathionine γ-lyase (CSE) increased Trx oxidation, promoted Trx binding to TXNIP and exaggerated cell injury caused by Trx inhibition. Collectively, our results indicate that H2S exerted its antioxidative effects through the regulation of the redox state of Trx and interference with Trx/ASK1/P38 signaling pathway. Given the importance of the pathway in the mediation of multiple oxidative cell responses, our study thus provides novel mechanistic insight into the action of H2S.